Skeletal-muscle-targeted non-viral delivery of full-length DMD mRNA for Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a severe, progressive muscle-wasting disorder caused by mutations in the DMD gene, which encodes dystrophin. Although gene therapy using viral vectors has shown promise for the treatment of DMD, the clinical application of viral gene therapies is limited by vector toxicity, immunogenicity and the inability to package full-length dystrophin. Recent advances in messenger RNA (mRNA) technology offer a non-integrating, transient approach to restoring protein expression. Here we report the systemic delivery of skeletal-muscle-targeted full-length DMD mRNA in a murine model of DMD using allogenically engineered targeting extracellular vesicles (DMD t-EVs). This approach restores the endogenous translation of wild-type dystrophin and substantially improves muscle function. We further demonstrate the safety and biocompatibility of DMD t-EVs in non-human primates, supporting their translational potential. These findings highlight the promise of mRNA-loaded extracellular vesicles as a therapeutic platform for treating genetic disorders involving large, difficult-to-package genes.